Anatomical variants of the intercostobrachial nerve and its preservation during surgery, a systematic review and meta-analysis

Background The anatomic variants of the intercostobrachial nerve (ICBN) represent a potential risk of injuries during surgical procedure such as axillary lymph node dissection and sentinel lymph node biopsy in breast cancer and melanoma patients. The aim of this systematic review and meta-analysis was to investigate the different origins and branching patterns of the intercostobrachial nerve also providing an analysis of the prevalence, through the analysis of the literature available up to September 2023. Materials and methods The protocol for this study was registered on PROSPERO (ID: CRD42023447932), an international prospective database for reviews. The PRISMA guideline was respected throughout the meta-analysis. A systematic literature search was performed using PubMed, Scopus and Web of Science. A search was performed in grey literature through google. Results We included a total of 23 articles (1,883 patients). The prevalence of the ICBN in the axillae was 98.94%. No significant differences in prevalence were observed during the analysis of geographic subgroups or by study type (cadaveric dissections and in intraoperative dissections). Only five studies of the 23 studies reported prevalence of less than 100%. Overall, the PPE was 99.2% with 95% Cis of 98.5% and 99.7%. As expected from the near constant variance estimates, the heterogeneity was low, I2 = 44.3% (95% CI 8.9%−65.9%), Q = 39.48, p = .012. When disaggregated by evaluation type, the difference in PPEs between evaluation types was negligible. For cadaveric dissection, the PPE was 99.7% (95% CI 99.1%–100.0%) compared to 99.0% (95% CI 98.1%–99.7%). Conclusions The prevalence of ICBN variants was very high. The dissection of the ICBN during axillary lymph-node harvesting, increases the risk of sensory disturbance. The preservation of the ICBN does not modify the oncological radicality in axillary dissection for patients with cutaneous metastatic melanoma or breast cancer. Therefore, we recommend to operate on these patients in high volume center to reduce post-procedural pain and paresthesia associated with a lack of ICBN variants recognition. Supplementary Information The online version contains supplementary material available at 10.1186/s12957-024-03374-w.


Introduction
The Intercostobrachial nerve (ICBN) emerges from the second intercostal space and it traverses the axilla horizontally [1,2].Then it perforates the deep fascia of the arm, providing the sensory supply to the upper medial region of the arm [3].The anatomy of ICBN represents a potential risk of unintentional injuries during routine surgical procedures such as axillary lymph node dissection (ALND) and sentinel lymph node biopsy (SLNB) [4].
Breast cancer stands as the most prevalent malignant in women throughout the world, affecting almost 12% of women in Western countries [5].The ICBN seems to be frequently damaged during mastectomy procedures and other techniques such as ALND (Axillary Lymph Node Dissection) and SLNB (Sentinel Lymph Node Biopsy); some studies suggest that injuring ICBN could play a role in Persistent Pain After Breast Cancer Treatment (PPBCT) and reduction of sensory function in the affected area [1,3].Additionally, the possibility of injury of the ICBN should also be considered in axillary surgery for melanoma [6].
Researchers have demonstrated that ICBN preservation significantly reduce post-procedural paresthesia and improve quality of life after the treatment for breast cancer and axillary surgery for melanoma.In fact, damaging ICBN or one of its primary branches could represents a cause of dysesthesia, paresthesia and chronic pain in these patients.Surgeons need to be accurate during the exploration of the axillary region, as the initial divisions and the connections between the ICBN and the brachial plexus may be damaged [3].The configuration of the ICBN has an important variability, showing multiple points of origin, patterns of division, and connections with other branches.If surgeons could know the real frequency, the characteristics of these division and the origin models of ICBN they could reduce the ICBN lesions and the post operatory morbility [3,4].
The aims of this systematic review and meta-analysis are to assess the prevalence, the different origins and branching patterns of the intercostobrachial nerve, analyzing the literature available up to the present day.

Search strategy
The protocol for this study was registered on PROSPERO (ID: CRD42023447932), an international prospective database for reviews.
The PRISMA (preferred reporting items for systematic reviews and meta-analyses) guideline was respected throughout the meta-analysis [7].The identification of articles to be included in the meta-analysis was carried out with searches up to September 2023 in the following databases: PubMed, Scopus and Web of Science.The search strategy performed in PubMed is presented as follows: nerve and Intercostobrachial or nervus intercostobrachialis.No date or language restrictions were applied.Identification of additional studies eligible for the metaanalysis was performed by searching the references of all included articles.

Evaluation of inclusion criteria
Eligibility for inclusion in this systematic review and meta-analysiss was performed by M.M. and R.C.All intraoperative or cadaveric studies reporting extractable prevalence data on the origin or branching of ICBN were included.Exclusion criteria included: case reports, case series, letters to the editor, or conference abstracts.

Data extraction
Data from the included studies were extracted by R.C. and M.M.For each article, the following information have been extracted: first author and year of publication, nation of study, sample size (number of patients and number of axillae analyzed), time of enrollment, type of study, type of evaluation (cadaveric or surgical), type of surgical treatment, prevalence of ICBN, origin of ICBN, mode of branching of ICBN.All selected full text articles were evaluated by quality assessment and analysis of the risk of bias using the Anatomical Quality Assurance (AQUA) [Henry, B.M. et al. 2017 [8]].

Study identification
The initial literature search identified 497 articles.Following the removal of duplicates and primary screening, 43 articles were assessed as full text for eligibility in the meta-analysis records.Finally, we included a total of 23 articles [2-4, 6, 9-27] selected by eliminating articles with incomplete information and articles that used different classification (Fig. 1).

Quality valutation of the studies included
The AQUA tool probes for potential risk of bias in 5 studies domains (objectives and subject characteristics, study design, methodology characterization, descriptive anatomy and reporting of results) (Henry, B.M. et al. 2017 [8]).The risk of bias within each domain is normally categorized as "Low", "High" or "Unclear".Twenty-two of the studies included showed low risk in domain one (Objectives and Subject characteristics), ten studies showed high risk of bias in domain three (Methodology characterization), mainly because there is an important reduction of possibility of studying anatomy during an intervention.A summary of the assessment of quality and risk of bias by the AQUA tool is displayed in the Fig. 2.

Statistical methods
For the primary outcome-prevalence of the ICBNpooled prevalence estimates (PPES) and their 95% confidence intervals are reported using MetaXL software (V.5.3).We used a DerSimonian and Larid random effects model with a double arcsin transformation, normalized prevalence, and a 0.5 continuity correction.Heterogeneity was investigated through the I 2 statistics, Cochrane's Q statistic, and a visual analysis of forest plots and funnel plots.In addition, we examined evaluation type (cadaveric dissection or intraoperative dissection) and geographic region of the first author's affiliation (Africa, Americas, Asia, Oceania, or Europe) as factors.A leaveone-out sensitivity analysis was conducted to examine the effect of outlying studies.Funnel plots and Doi plots were used to investigate possible sources of bias-including publication bias.The leave-one-out sensitively analyses yielded PPEs from 99.3% with the Andersen 2014 [19] study excluded to 99.1% with the Loukas et al. 2016 [23] study excluded.There was great variety in the outcome categories that authors used in the secondary outcomes: this is the reason why a single multicategory pooled prevalence estimate was not possible for any secondary outcomes.Furthermore, it was not feasible to report on the PPEs for tens of secondary outcomes if each of the outcome categories were reported as individual binary outcomes.Therefore, we descriptively report the secondary outcomes using only raw, marginal proportions.

Sensorial analysis Pain in patients with intercostobrachial nerve section
Postoperative pain was assessed at the time of discharge (7 studies, 209 ICBN) and after 3 months (4 studies, 92 ICBN).Postoperative pain was present in 38.75% at discharge and 46.74% after 3 months from the procedure (Fig. 9).

Hypoesthesia in patients with intercostobrachial nerve section
The decrease in postoperative sensitivity was evaluated at the time of discharge (5 studies, 169 ICBN) and after 3 months (4 studies, 105 ICBN).Postoperative hypoesthesia was present in 62.13% at the time of discharge and 51.42% after 3 months from the procedure (Fig. 9).

Paresthesia in patients with intercostobrachial nerve section
The presence of postoperative paresthesia was assessed at the time of discharge (9 studies, 283 ICBN) and after 3 months (2 studies, 42 ICBN).Postoperative paresthesia was present in 40.99% at the time of discharge and 10.04% after 3 months from the procedure (Fig. 9).

Pain in patients with intact intercostobrachial nerve
Postoperative pain was assessed at the time of discharge (7 studies, 288 ICBN) and after 3 months (4 studies, 103 ICBN).Postoperative pain was present in 31.59% at discharge and 12.62% after 3 months (Fig. 10).

Hypoesthesia in patients with intact intercostobrachial nerve
The decrease in postoperative sensitivity was evaluated at the time of discharge (5 studies, 228 ICBN) and after 3 months (4 studies, 123 ICBN).Postoperative hypoesthesia was present in 45.17% at discharge and 18.70% after 3 months (Fig. 10).

Paresthesia in patients with intact intercostobrachial nerve
The presence of postoperative paresthesia was assessed at the time of discharge (8 studies, 321 ICBN) and after 3 months (3 studies, 57 ICBN).Postoperative paresthesia was present in 29.6% at discharge and 22.8% after 3 months (Fig. 10).

Discussion
The intercostobrachial nerve (ICBN) is an anatomical structure with a high variability in origin and branching pattern.The ICBN is a branch of the second intercostal nerve: therefore, special attention should be paid to the area of the second intercostal space, where the origin of the ICBN is most likely (90.6%).However, the ICBN could present occasional contribution also from the third intercostal nerve and it can be identified in an anterior position during the exposure of the thoracic and thoracodorsal long nerves.The ICBN is at high risk of injury during operative procedures into the axilla.ICBN fiber's injury has been associated with post-procedural pain, paresthesia and with a reduction of the quality of life.The evaluation of prevalence of ICBN might have an impact on surgical plan and patient outcomes: in fact, lymphedema, motor and/or sensor alterations of the arm have an impact on the quality of life of patients who underwent to operative procedure into the axillary region.Moderate or severe post-operative pain is experienced by 50% of patients after breast surgery (Andersen; Besic).
The ICBN should always be preserved.However, current guidelines do not provide specific recommendations regarding the preservation or sacrifice of the ICBN during axillary lymph-node dissection or sentinel lymphnode biopsy.A study conducted by Henry et al. in 2017 [29] showed that the ICBN is a variable structure at risk for injury during operative procedures of the axilla and due to the postoperative pain and paresthesia experienced by patients following injury, surgeons need to exercise caution and need to preserve the ICBN.Another study, conducted by Warrier et al. in 2014 [30] showed that the incidence of sensory disorder was lower in case of preservation of ICBN compared with the division of the ICBN.
On the other hand, in three different studies, conducted respectively by Abdullah et al. 1998 [31], Salmon et al. 1998 [32] and Torresan et al. 2003 [24], showed that patients who presented sensory distur in the immediate post-operative period may have a resolution of the symptoms and patients who may not notice any sensory disturbance initially may develop it at a later stage.
The ICBN can be damaged for a variety of reasons, from traction to transection.In addition, damaged nerves can develop neuromas that can further complicate the patient' symptoms.
Our systematic review and meta-analysis showed that the overall prevalence of ICBN was 98.94% and that more frequently it exists as a single trunk (51.6%) originating from the T2 vertebral level (81.79%).The branching subgroups are differently based on the type of the study (cadaveric or operational).In fact, we noticed that the ICBNs examined in cadavers (99.8%) had a bifurcation rate more than double than those evaluated during operation (98.63%).
From these differences we deduced two different hypotheses.Firstly, the limited intraoperative field of view and the inability to freely dissect tissue without consequences may limit the in vivo identification of the nerve branches.These differences may help to explain the reason why post-operative complications might be present even if nerves are successfully identified and protected.Kumar et al. 2016 [3] noted that, six months after surgery, 20% of patients who had successfully preserved ICBN still had numbness and paresthesia.The ICBN may also be damaged due to stretching by retractors or other intraoperative stresses on nerve fibers.Secondly, ICBN might have a propensity to bifurcate unequally when analyzing cadaveric or intraoperative studies (63.4% unequal bifurcation versus 36.6% equal bifurcation).Therefore, surgeons can easily identify the larger trunk, but a failure to identify the smaller branch puts it at high risk of operative injury.
Our meta-analysis was limited by several factors related to inconsistent reporting and small sample sizes.Some studies presented the origins of the first or third intercostal nerve as separate data.It was unclear whether these origins were duplications or simply contributing fibers and therefore were excluded from the present analysis.In addition, we observed a high heterogeneity which might have the result of an inherent variable nature of the ICBN course.Another limitation of our study is the lack of data regarding the preservation of the intercostobrachial nerve during SLNB.However, larger studies are needed to demonstrate this observation.
Furthermore, in our analysis, cadaveric dissection rather than intraoperative dissection was more specific in the demonstration of multiple branching pattern.In fact, anatomical data retrieved from operative field were less accurate.Probably this rate discrepancy was associated to reporting errors.
In general, the studies did not provide information on factors such as sex and laterality, which could allow further subgroup analyses.Most studies have been conducted on women; however, Loukas et al. 2006 [23] found no gender differences.Limited data from regions such as Africa, North America, Oceania, and South America precluded analysis of other regions besides Europe and Asia.Many studies have a lack of detailed data on the branching site or symmetry of post-division branches.
Future studies need to be carried out to further elucidate the behavior of the terminal branching of the ICBN and its anastomoses with the brachial plexus.There is also the possibility of studying the use of landmarks or relationships with adjacent structures to be able to intraoperatively identify the nerves.Structures such as the lateral thoracic vein discussed in O'Rourke et al. 1999 [27] could be a potential candidate.Integration with future research will provide valuable information for surgeons and, ideally, lead to more positive outcomes for patients undergoing surgeries in the axillary region.In fact, ICBN neuralgia and post-operative pain syndrome can be successfully managed with locoregional anesthesia techniques, but the primary goal should be the overall reduction of their incidence.
An accurate knowledge of the anatomy of axillary region is crucial to reduce nerve' injuries.Another possible strategy for minimizing nerve' injuries during surgery could be the ultrasound guided identification of ICBN before surgery.In fact, in a study conducted by Feigl et al. the ICBN blocks with ultrasound guided anterior approach to intercostal nerves was evaluated to supplement the axillary block.The sonographic identification of ICBN and its possible anatomical variations may be useful to reduce ICBN's injuries [33].
Furthermore, the group with intact ICBN have a higher percentage of paresthesia (32.8%) after three months than the group with ICBN section.We were unable to explain this result, but we think that this pain might be similar to groin pain after inguinal hernia repair [34].For this reason, some surgeons suggest to perform the inguinal nerve neurectomy in all patient underwent open mesh hernia repair [35].

Conclusion
The prevalence of ICBN is very high, for this reason during axillary dissection a small operative theatre is associated at the inability to freely dissect tissue without a reduction of post-procedural pain and paresthesia.The division of the ICBN during axillary lymph node dissection, increases the risk of sensory disturbance such as hyposensitivity of the arm.The preservation of the ICBN do not modify the oncological radicality in axillary dissection for patients with cutaneous metastatic melanoma or breast cancer.

Fig. 1
Fig. 1 Prisma flow diagram of studies included

Table 1
Characteristics of the included studies NR Not Rated, RCT Randomized Control Trial, OR Observational Retrospective, OP Observational Prospective, P Prospective, R Retrospective, ANDBC Axillary Node Dissection performed during surgery for Breast

Cancer Author/Year Nation Time of enrollment Type of study Type of evaluation Type of surgical treatment
Fig. 2 Assessment of quality and risk of bias by the AQUA tool

Table 2
Studies with reported data on the origin of the ICBN

Table 3
Studies wich reported data on the ICBN branching pattern